Methods for treating otic disorders by local administration of a neurotoxin. A botulinum toxin can be administered to myoclonic middle ear muscles and to inner ear efferent and/or afferent nerves to alleviate otic disorders such as tinnitus, cochlear nerve dysfunction and Meniere""s disease.

The present invention relates to methods for treating otic disorders. In particular the present invention relates to methods for treating otic disorders by local administration of a neurotoxin to a human ear.
The human ear can be divided into an outer ear, a middle ear and an inner ear. The outer ear comprises the auricle (commonly referred to as the ear) and the external acoustic meatus (the auditory canal). The tympanic membrane (commonly called the eardrum) separates the auditory canal from the middle ear (the tympanic cavity). Three small, mobile bones, the incus, malleus and stapes make up an ossicular system which conducts sound through the middle ear to the cochlea. The handle of the malleus is attached to the center of the tympanic membrane. At its opposite end, the malleus is bound to the incus by ligaments, so that movement of the malleus causes the incus to also move. The opposite end of the incus articulates with the stem of the stapes. The faceplate of the stapes rests against the membranous labyrinth in the opening of the oval window, where sound waves are conducted into the inner ear. In the cochlea the sound waves are transduced into coded patterns of impulses transmitted along the afferent cochlear fibers of the vestibulocochlear nerve for analysis in the central auditory pathways of the brain.
The air filled tympanic cavity contains various muscles including the tensor tympani and stapedius muscles. The tensor tympani is a long slender muscle which occupies the bony canal above the osseous pharyngotympanic tube, from which it is separated by a thin bony septum. The tensor tympani muscle receives both motor and proprioceptive innervation. A motor branch derived from the nerve to the medial pterygoid (mandibular division of the V, parasympathetic, trigeminal nerve) passes through the otic (a peripheral, parasympathetic cholinergic) ganglion to the tensor tympani. The stapedius muscle extends from the wall of a conical cavity in the pyramidal eminence, located on the posterior wall of the tympanic cavity. The stapedius is innervated by a branch of the (VII, parasympathetic) facial nerve.
Middle ear structures can be examined endoscopically, as set forth by Karhuketo et al., Endoscopy of the Middle Ear Structures, Acta Otolaryngol (Stockh) 1997; Suppl 529:34-39, the contents of which publication are incorporated herein by reference. There are many diseases of the ear including otis media. Otis media is an inflammation of the middle ear, commonly due to infection, and treatable by antibiotics. Alternate treatments for otis media include analgesics, antipyretics and myringotomy.
Loud noise can cause a muscular reflex to arise which attenuates the effect of excessive loud sound upon the middle and inner ear. Thus, the tensor tympani muscle can contract and pull the handle of the malleus inward while the stapedius muscle contracts and pulls the stapes outward. These two forces oppose each other and result in a high degree of rigidity developing in the ossicular system, thereby greatly reducing (by about 30-40 decibels) conduction of low frequency sounds by the ossicular system. This attenuation reflex can protect the cochlea against the damaging vibrations which would otherwise be induced by loud noise and may also act, mask out low frequency sound in a loud environment, and decrease a person""s hearing sensitivity to his own voice.
The inner ear comprises the osseous labyrinth and the contained membranous labyrinth. The osseous labyrinth has three regions, the vestibule, the semicircular canals and the cochlea. The membranous labyrinth can be divided into the vestibular apparatus and the cochlear duct. In the walls of the membranous labyrinth within the vestibular apparatus are five distinct area of specialized sensory epithelium to which the terminal fibers of the vestibular nerve are distributed. Hair cells (epitheliocyti pilosi) in the cochlea are the sensory transducers which collectively detect the amplitude and frequency of sound waves entering the cochlea. The efferent innervation of at least the outer hair cells is cholinergic. Afferent innervation of the hair cells is complex and may involve release of one or more neurotransmitters, including glutamate.
Tinnitus
Tinnitus is a perception of sound which originates in the head. It has been estimated that 36 million Americans have some form of tinnitus and that one third of these have severe tinnitus, that is 12 million Americans hear tinnitus all he time (Vernon. J. A., Tinnitus Treatment and Relief, Allyn and Bacon (1998)). In objective tinnitus, the sound is audible, can be heard upon examination of the patient, and frequently corresponds to respiration. In the more frequent subjective tinnitus the sound cannot be heard by someone other than the patient. Tinnitus can be due to myoclonus of the palatal, tensor tympani and/or stapedius muscles.
Myoclonus is a sudden, involuntary movement caused by a muscle contraction or muscle inhibition and can be classified as physiologic, essential, epileptic and symptomatic myoclonus. Palatal myoclonus is characterized by involuntary movements of the soft palate and pharynx. The rhythmic involvement of the eustachian tube can result in the production of audible clicking sound synchronous with the palatal myoclonus. In palatal myoclonus the patient hears an irregular clicking sound coming form one or both ears. The condition is caused by myoclonic contractions in tensor or levator palati muscles or both. The injection of botulinum toxin into the soft palate has been effective to treat palatal myoclonus.
Myoclonus of the middle ear is characterized by abnormal repetitive muscle contractions in the tympanic cavity and can result in subjective or objective tinnitus. Permanent relief has been obtained by sectioning or by lysis of the tendons of the stapedius and tensor tympani muscles.
Inner ear tinnitus has been treated by section of the auditory nerve. Animal studies have shown that drugs, such a aspirin, which are known to cause tinnitus, do so with an increase in activity of the auditory nerve. It has therefore been speculated that a decrease in the endocochlear potential by down regulation of the auditory nerve may alleviate tinnitus.
A particular form of inner ear tinnitus is cochlear synaptic (cochlear nerve dysfunction) tinnitus which is due to functional disturbances of the synapse between cochlear hair cells and afferent dendrites of the auditory nerve. The neurotransmitter at the afferent cochlear synapse is glutamate. The majority of patients with cochlear synaptic tinnitus intravenously infused with the glutamate antagonists glutamic acid diethyl ester and caroverine have noted a tinnitus reduction. Drug therapy for inner ear tinnitus has included benzodiazepine tranquilizers such as valium and Xanas (alprazolam), a powerful anxiolytic drug which has strong addictive properties and can cause personality changes. The local anesthetic lidocaine has been proven to relive tinnitus. Unfortunately, because of serious toxicity, lidocaine must be given intravenously and it""s effect lasts for only about 5-30 minutes.
Tensor tympani syndrome is a condition in which increased tension in the tensor tympani muscle produces a fluttering low frequency sound in the ear. In many cases the sound is also felt, as if there is a fluttering insect in the bottom of the ear canal. This is caused by the tympanic membrane being rapidly moved by the fibrillation of this middle ear muscle. Therapy includes section of the tendon of the tensor tympani muscle behind the neck of the malleus.
Tinnitus resulting from Meniere""s disease can be treated by sectioning the vestibular nerve. Auditory nerve section has been used as a means of treating intractable tinnitus, often with the condition worsening because the tinnitus was not due to a cochlea disorder, prior to irreversible ablative surgery, after which no residual hearing will remain in the ear operated upon.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of botulinum toxin (purified neurotoxin complex) type A1 is a LD50 in mice. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD50 for botulinum toxin type A. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. Botulinum toxin type A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus and hemifacial spasm. Non type A botulinum toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to botulinum toxin type A. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin type C1 has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes.
The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C1 is apparently produced as only a 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine, CGRP and glutamate.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In contrast, botulinum toxin serotypes C1, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the botulinum toxin type B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the botulinum toxin type B toxin is likely to be inactive, possibly accounting for the known significantly lower potency of botulinum toxin type B as compared to botulinum toxin type A. The presence of inactive botulinum toxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that botulinum toxin type B has, upon intramuscular injection, a shorter duration of activity and is also less potent than botulinum toxin type A at the same dose level.
It has been reported that botulinum toxin type A has been used in clinical settings as follows:
(1) about 75-125 units of BOTOX(copyright) per intramuscular injection (multiple muscles) to treat cervical dystonia;
(2) 5-10 units of BOTOX(copyright) per intramuscular injection to treat glabellar lines (brow furrows) (5 units injected intramuscularly into the procerus muscle and 10 units injected intramuscularly into each corrugator supercilii muscle);
(3) about 30-80 units of BOTOX(copyright) to treat constipation by intrasphincter injection of the puborectalis muscle;
(4) about 1-5 units per muscle of intramuscularly injected BOTOX(copyright) to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
(5) to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 units of BOTOX(copyright), the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. amount of diopter correction desired).
(6) to treat upper limb spasticity following stroke by intramuscular injections of BOTOX(copyright) into five different upper limb flexor muscles, as follows:
(a) flexor digitorum profundus: 7.5 U to 30 U
(b) flexor digitorum sublimus: 7.5 U to 30 U
(c) flexor carpi ulnaris: 10 U to 40 U
(d) flexor carpi radialis: 15 U to 60 U
(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX(copyright) by intramuscular injection at each treatment session.
What is needed therefore is an effective, non-surgical ablation, non-radiotherapy therapeutic method for treating otic disorders, including middle ear tinnitus, inner ear tinnitus and myoclonic ear muscle tinnitus.
The present invention meets this need and provides an effective, non-surgical ablation, non-radiotherapy therapeutic method for treating otic disorders, including middle ear tinnitus, inner ear tinnitus, and myoclonic ear muscle tinnitus.
A method within the scope of the present invention for treating an otic disorder has the step of local administration of a neurotoxin to an ear of a patient. By local administration it is meant that the neurotoxin is administered, as by injection, directly to, in, or to the vicinity of, the region of the ear to be treated. Preferably, the neurotoxin is injection into the middle or inner ear since otic disorders predominate in these areas.
The neurotoxin can be locally administered in an amount of between about 10xe2x88x923 U/kg of patient weight and about 35 U/kg of patient weight. Preferably, the neurotoxin is locally administered in an amount of between about 10xe2x88x922 U/kg and about 25 U/kg. More preferably, the neurotoxin is administered in an amount of between about 10xe2x88x921 U/kg and about 15 U/kg. In a particularly preferred method within the scope of the present invention, the neurotoxin is locally administered in an amount of between about 1 U/kg and about 10 U/kg. In a clinical setting it can be advantageous to inject from 1 U to 10 U of a neurotoxin, such as botulinum toxin type A, into a middle or inner ear structure to effectively treat an otic disorder.
A suitable neurotoxin for use in the practice of the present invention can be made by a Clostridial bacterium, such as Clostridium botulinum, Clostridium butyricum or Clostridium beratti. The neurotoxin use can be a modified neurotoxin, that is a neurotoxin has had at least one of its amino acids deleted, modified or replaced, as compared to a native neurotoxin. Additionally, the neurotoxin can be recombinantly made produced neurotoxin or a derivative or fragment of a recombinant made neurotoxin. The neurotoxin can be a botulinum toxin, such as one of the botulinum toxin serotypes A, B, C1, D, E, F or G. A preferred botulinum toxin to use in the practice of the present invention is botulinum toxin type A.
The otic disorder treated can be a hearing impairment, tinnitus, vertigo, dizziness and/or headache and the neurotoxin can is locally administered to the outer ear, the middle ear or the inner ear. A method for treating tinnitus within the scope of the present invention can comprise the step of local administration of a therapeutic amount of a botulinum toxin to the middle or inner ear of a human patient to thereby substantially alleviating the tinnitus. The tinnitus can be treated by local administration of a botulinum toxin to a myoclonic middle ear muscle, such as a myoclonic stapedius or tenor tympani muscle.
A detailed method within the scope of the present invention for in vivo treatment of a non-infectious disorder of the middle or inner ear of a human patient can comprise the step of local administration to the middle ear or inner ear of the human patient of a therapeutically effective amount of a botulinum toxin, thereby causing or resulting in an in vivo attenuation of the non-infectious middle or inner ear disorder of the human patient. A further method within the scope of the present invention is a method for improving patient function, the method comprising the step of administering a neurotoxin to an ear of a human patient, thereby improving patient function as determined by improvement in one or more of the factors of reduced pain, reduced time spent in bed, improve hearing, increased ambulation, healthier attitude and a more varied lifestyle.
Notably, the disclosed methods can be used to treat inner ear otic disorders such as Meniere""s disease and cochlear nerve dysfunction.
The present invention is based upon the discovery that otic disorders, such as some forms of tinnitus, can be treated by local administration of a neurotoxin, such as a botulinum toxin. By local administration it is meant that the neurotoxin is administered directly to, in, or to the vicinity of, the ear or ear region to be treated. Local administration includes otic intramuscular, intratympanic cavity and intracochlear injection routes of administration for the neurotoxin. Peripheral (i.e. limb) muscle intramuscular, intrasphincter (i.e. in the GI tract), oral, and subcutaneous drug administration routes are unsuited for the practice of the present invention and are excluded from its scope.
The present invention is not intended for the treatment of an infectious otic disorder, such as otis media, because the neurotoxins administered do not exhibit an antibiotic effect. It is known to inject or infuse antibiotics into the tympanic cavity, as set forth, for example in Otolaryngol Head Neck Surg. 1999 May;120(5):649-55, and Am J Otol 1997 Sep;18(5):586-9, the contents of which two publications are incorporated herein by reference in their entireties.
I have discovered that a particular neurotoxin, botulinum toxin, can be used with dramatic ameliorative effect to treat tinnitus thereby significantly superseding current surgical and radiotherapy therapeutic methods used to treat tinnitus. Significantly, a single administration of the botulinum toxin can substantially also reduce the headache, vertigo and anxiety symptoms which can accompany tinnitus.
The route of administration and amount of botulinum toxin administered can vary widely according to the particular otic disorder being treated and various patient variables including size, weight, age, disease severity and responsiveness to therapy. Additional factors affecting determination of an appropriate route for administration of a neurotoxin according to the present disclosed invention for treating an otic disorder can include solubility characteristics of the neurotoxin toxin chosen as well as the amount of the neurotoxin to be administered. For example, the extent of otic muscle or nerve area influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the denervation is, for most dose ranges, believed to be proportional to the concentration of neurotoxin injected. The specific dosage appropriate for administration is readily determined by one of ordinary skill in the art according to the factor discussed above. The dosage can depend upon the size of the muscle to be denervated, the degree of weakness required and the commercial preparation of the toxin. Additionally, the estimates for appropriate dosages in humans can be extrapolated from determinations of the amounts of botulinum required for effective denervation of other non-otic muscles.
Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison""s Principles of Internal Medicine (1997), edited by Anthony Fauci et al., 14th edition, published by McGraw Hill). For example, to treat tinnitus due to a myoclonic middle ear muscles, a solution of botulinum toxin type A complex can be endoscopically administered intramuscular directly to the hyperactive muscle, thereby substantially avoiding entry of the toxin into the systemic circulation.
Preferably, a neurotoxin used to practice a method within the scope of the present invention is a botulinum toxin, such as one of the serotype A, B, C1, D, E, F or G botulinum toxins. Preferably, the botulinum toxin used is botulinum toxin type A, because of its high potency in humans, ready availability, and known use for the treatment of skeletal and smooth muscle disorders when locally administered by intramuscular injection.
Careful placement of the injection needle and a low volume of neurotoxin used prevents significant amounts of botulinum toxin from appearing systemically. The actual amount of U/kg of a botulinum toxin to be administered depends upon factors such as the extent (mass) of the otic tissue to be treated and the administration route chosen. A range for direct otic administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve an alleviation of middle ear tinnitus, inner ear tinnitus in the patient treated is from about 10xe2x88x923 U/kg to about 35 U/kg. Less than about 10xe2x88x923 U/kg result in a relatively minor, though still observable, therapeutic results (i.e. alleviation of myoclonia), while more than about 35 U/kg can result in excessive peripheral muscle flaccidity and symptoms of toxin intoxication. A more preferred range for intrathecal administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a desired therapeutic effect in the patient treated is from about 10xe2x88x922 U/kg to about 25 U/kg. Less than about 10xe2x88x922 U/kg result in a low to moderate therapeutic results while more than about 25 U/kg can result in significant symptoms of peripheral muscle flaccidity. A most preferred range for direct administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a desired therapeutic effect in the patient treated is from about 10xe2x88x922 U/kg to about 15 U/kg. More than about 15 U/kg can still result in some symptoms of muscle flaccidity.
The relatively same size and mass of the stapedius and tensor tympani muscles makes a range of from about 1 U to about 50 U (total units) suitable of a botulinum toxin, such as botulinum toxin type A, preferred for effective for long lasting and significant relief from the tinnitus due to specifically to myoclonic stapedius and tensor tympani muscles. A more preferred range for effective for long lasting and significant relief from the tinnitus due to specifically to myoclonic stapedius and tensor tympani muscles is from about 1 U to about 25 U (total units). All dosage amount set forth about are per injection. Most preferably, considering the small size of the stapedius and tensor tympani muscles, from about 1 U to about 10 U per injection (i.e. once every 2-6 months) of intramuscular botulinum toxin type A can be injected into each of these two middle ear muscles to thereby provide substantial relief from tinnitus.
The present invention includes within its scope the use of any neurotoxin which has a long duration therapeutic effect when locally applied to an otic region or structure of a patient. For example, neurotoxins made by any of the species of the toxin producing Clostridium bacteria, such as Clostridium botulinum, Clostridium butyricum, and Clostridium beratti can be used or adapted for use in the methods of the present invention. Additionally, all of the botulinum serotypes A, B, C1, D, E, F and G can be advantageously used in the practice of the present invention, although type A is the most preferred serotype, as explained above. Practice of the present invention can provide a significant therapeutic effect, per injection, for 2-6 months or longer in humans.
The therapeutic relief provided by a single injection of botulinum toxin type A has been demonstrated to last at least as long as 27 months, and possibly permanently for some types of disorders depending upon the site and dosage injected, among other factors. Hence, it is within the scope of the present invention to provide long lasting therapeutic relief from an otic disorder by the methods disclosed herein.
It is the inventor""s contention that a botulinum toxin can block the release of any vesicle mediated exocytosis from any neuronal cell type, as long as the light chain of the botulinum toxin is translocated into the intracellular medium. For example, the intracellular protein SNAP-25 is widely distributed in neuronal cells and botulinum toxin type A is an endopeptidase for which the specific substrate is SNAP-25. Thus, while cholinergic neurons have a high affinity acceptor for the botulinum and tetanus toxins (and are therefore more sensitive than other neurons and other cells to the inhibition of vesicle mediated exocytosis of secretory compounds), as the toxin concentration is raised, non-cholinergic sympathetic neurons can take up a botulinum toxin and show reduced exocytosis of neurotransmitters other than acetylcholine.
Hence, by practice of the present disclosed invention, non-cholinergic inner ear nerve fibers can be treated by use of an appropriately higher concentration of a botulinum toxin to bring about therapeutic inner ear denervation (i.e. effective treatment of inner ear tinnitus).
Furthermore, a method within the scope of the present invention can provide improved patient function. xe2x80x9cImproved patient functionxe2x80x9d can be defined as an improvement measured by factors such as a reduced pain, reduced time spent in bed, increased ambulation, healthier attitude, more varied lifestyle and/or healing permitted by normal muscle tone.
The present invention includes within its scope: (a) neurotoxin complex as well as pure neurotoxin obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying (or vacuum drying) and/or reconstitution and; (b) modified or recombinant neurotoxin, that is neurotoxin that has had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made, and includes neurotoxins with one or more attached or recombinantly fused neuronal targeting moieties.
Botulinum toxins for use according to the present invention can be stored in lyophilized or vacuum dried form in containers under vacuum pressure. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized or vacuum dried material can be reconstituted with saline or water.
The present invention can be practiced by transtympanic injection of botulinum toxin to reduce activity and tone of transtympanic muscles and thereby treat tinnitus, dysacusis (which can be defined as abnormal acoustic sensations, such as murmurs, clicks, tickling sensations and sound distortions, as well as pain or discomfort in the ear due to exposure to sound), tension headache, and vertigo (dizziness and dysequilbrium).
Without wishing to be bound to any particular theory, the mechanism of botulinum toxin activity upon middle ear tinnitus is believed to be by exertion of an anticholinergic effect. Thus, the stapedius muscle is innervated by cholinergic motor neurons derived from the facial nerve, while the tensor tympani muscle is innervated cholinergic motor neurons branching from the trigeminal nerve through the otic ganglion. A possible similar mechanism of action of botulinum toxin to treat inner ear tinnitus can be postulated. Hair cell efferents are believed to be influenced by acetylcholine and hair cell afferents may release glutamate. I have discovered that tinnitus resulting from abnormal neuronal activity of, or influence upon, inner ear hair cells can be treated by suppressing exocytosis in inner ear nerve fibers of the indicated neurotransmitters. Exocytosis is suppressed by local administration of a neurotoxin by the methods set forth herein.
A significant and important benefit of the disclosed invention is that it supercedes and renders unnecessary much highly invasive surgery. Thus, endoscopic and EMG recording, as opposed to open (i.e. craniotomy and dural incisions) surgical means (as opposed to the nominal invasive nature of a transtympanic approach) are used to access and treat a middle ear muscle (treatment of middle ear tinnitus) or the cochlea (treatment of inner ear tinnitus).
Endoscopic assisted (including laser assisted endoscopy to make an incision in the tympanic membrane) injection of a botulinum toxin to a middle or inner ear structure of a patient to treat an otic disorder according to the present invention can be carried out by application of or by facile adaptation of known endoscopic procedures, as set forth for example in Amer J. Otology 16 (2); 158-163 (March 1995), and Ear Nose Throat J. 76(9) 674-678 (September 1997), the contents of which two publications are incorporated herein by reference in their entireties.
Besides endoscopic assisted local administration of a neurotoxin to treat an otic disorder, the present methods can be practiced by injection through the tympanic membrane using a fine (EMG recording) needle, through use of an indwelling catheter placed through a myringotomy incision, and injection or infusion through the Eustachian tube by means of a small tubal catheter. Additionally, a neurotoxin can be administered to the inner ear by placement of a gelfoam, or similar absorbent and adherent product, soaked with the neurotoxin against the round window membrane of the middle/inner ear or adjacent structure.

Neurotoxin therapy for inner ear disorders


Selectively colorable compositions and a method for forming selectively colored polymeric bodies using such compositions are disclosed. In accordance with the invention, a selectively colorable polymerizable composition comprising a leucobase color former is irradiated with light of a particular wavelength and specific intensity for a specified duration. Exposure to actinic radiation cures the composition and activates the color former. Exposure to higher dosages of actinic radiation can bleach the composition. The irradiation dosage can be varied to selectively color the polymeric body whereby the resultant color of any particular area depends on the exposure dose received at that location. By varying the dose, a polymeric body can be prepared having distinctly colored elements at specific locations.

The present invention relates to selectively colorable compositions and to a method for forming selectively colored polymeric bodies using such compositions.
Commonly assigned U.S. Pat. No. 5,942,554 discloses a curable composition containing a color precursor and an onium salt which is both cured and colored upon exposure to actinic radiation. Color precursors disclosed as being useful are those which are capable of reacting with acid or whose excited states are capable of donating an election.
Commonly assigned U.S. patent application Ser. No. 09/558,599 filed on Apr. 26, 2000, now U.S. Pat. No. 6,309,797 discloses selectively colorable polymerizable compositions comprising a leucobase color former and a leuconitrile color former. Irradiation of the composition cures and selectively colors the composition. The color at any one location depends on the actinic dose and the interaction of the leucobase and leuconitrile colorformers. In one embodiment, a selectively colorable, polychromic composition is provided wherein low light exposure creates a polymer of one color, intermediate light exposure changes the color of the polymer and a high dosage of light exposure bleaches the color of the polymer.
International Publication Number WO 97/09168 to Zeneca discloses a photocurable, photocolorable composition which is irradiated with a low dose of light to cure and a different dose of light, preferably higher, to cause color formation. Color formation or color change occurs as a result of contact between a colorformer and a photochemically generated developer. The colorformers disclosed as being useful include lactones, fluorans, etc. which are acid sensitive compounds.
A selectively colorable solid object is an object that can be colored at small individual, but specifically defined, sites by irradiating light of a particular wavelength and specific intensity for a specified duration. The light sources capable of producing the selectively colorable solid object include: (a) a laser interfaced with an XY scanner (for polymer films), (b) a laser interfaced with an XYZ scanner (for 3D parts), (c) digital mirror device, (d) UV and Visible lamps with a masking device, etc.
A selectively colorable resin (SCR) system consists of: (a) the matrix (a blend of polymerizable material or a solid polymer), (b) a color former, (c) a color initiator (species that generate other species capable of reacting with color former; may not be needed in some systems); and (d) a chain reaction initiator (radical or cationic or none depending on the system).
The conventional method for forming a colored plastic body is to add a dye or pigment to the liquid prepolymer composition. The composition is then cured with actinic radiation. The latter requires that the absorption spectra of the photoinitiator and the dye/pigment differ. If the dye/pigment absorbs actinic radiation at the same wavelength as the photoinitiator, slower or no cure will be achieved. The color formation method is also not selective. The entire plastic is uniformly colored. Still another problem is that the photopolymerization process requires actinic radiation, but the color forming process requires only that the composition be well mixed. Though one of the processes can be controlled by the intensity/wavelength of the actinic radiation, the other is unaffected by it. Thus there is no selectivity of color formation in the plastic body.
Accordingly, there is a need for selectively colorable polymerizable compositions and for a method of forming selectively colored polymeric bodies using such compositions wherein the colorization process can be controlled as to the location and intensity of the color formed.
The present invention discloses selectively colorable compositions and a method for forming selectively colored polymeric bodies using such compositions. In accordance with the invention, a selectively colorable polymerizable composition comprising a leucobase color former and an oxidizing agent is irradiated with light of a particular wavelength and specific intensity for a specified duration. Exposure to actinic radiation cures the composition and activates the color former which can be optionally deactivated or bleached by further exposure. The irradiation dosage can be varied to selectively color the polymeric body whereby the resultant color of any particular area depends on the exposure dose received at that location. By varying the dose, a polymeric body can be prepared having distinctly colored elements at specific locations.
It is believed that, upon irradiation of the polymerizable composition of the present invention containing a polymerizable compound, a leucobase color former and an onium salt, two processes occur for color formation and bleaching. One process generates a dye cation via electron transfer process upon exposure of a leucobase dye precursor in the presence of an oxidizing agent and a second process is the bleaching of the dye cation upon further exposure. Accordingly, the composition of the present invention provides a photopolymerizable selectively colorable system. The bleaching process is efficient only when the starting material is an acid non-sensitive leucobase. The initial color is formed by a photooxidation process which involves electron transfer from the leucodye to the oxidizing agent. The bleaching process is not nearly as efficient in the case when the starting material is a dye or an acid-sensitive dye.
Under low dosage, color formation depends primarily on Scheme 1 wherein exposure of a leucobase to light in the presence of a oxidizing agent yields a dye cation. The mechanism is illustrated below for a triarylmethane (TAM) leucobase (TAMH) susceptible to oxidation. Ox represents an oxidizing agent, TAM+ represents the colored species and hv represents exposure to actinic radiation. It is anticipated that the scheme below will also be valid for diarylmethane (DAM) and other photooxidizable leucodyes which do not form the color with acid on contact.
TAMH+Ox+hxcexdTAM+(colored)xe2x80x83xe2x80x83Scheme 1
At higher doses of irradiation, bleaching of TAM+ occurs (Scheme 2). Therefore, the color of the polymeric body at higher doses disappears and the contrast is produced.
(TAM)++hxcexd bleaching products (colorless)xe2x80x83xe2x80x83Scheme 2
In another embodiment of the present invention, the oxidation process can be inhibited significantly by the introduction of at least one electron-withdrawing group (e.g., halogen, NO2, COR, COOR, etc., where R is H, hydrocarbon, etc.) to the TAM-H or DAM-H aromatic structure. In this case, color formation is delayed allowing one to obtain colorless polymer at low doses, colorize the polymer at an intermediate dose and bleach the color by further irradiation.
In accordance with the present invention, a composition which can be selectively colored by exposure to actinic radiation and a method leading to the formation of selectively colored, polymer bodies that can be cured photochemically are provided. The invention is particularly useful for the selective color development and photopolymerization of films using a leucobase color former and an oxidizing agent. The composition of the present invention can be used in a solid or a liquid.
Those skilled in the art will appreciate that the color determinative irradiation step can be conducted before, after or simultaneously with the polymerization or crosslinking step. Furthermore, selective coloration of a polymeric body in accordance with the present invention can be carried out using one exposure or light source to polymerize or crosslink the composition and a second exposure or light source to induce the photochromic response, or using a single light source to polymerize the composition at a first intensity and using the same light source at a plurality of intensities to induce the photochromic response. The latter system has the advantage that it involves the use of only one light source and it will be appreciated that this system is easily implemented using highly sensitive photohardenable systems, which can be easily polymerized using a lower intensity light exposure. As a general rule, agents, such as photoinitiators, used to initiate polymerization will be more efficient than the photoresponsive agents described below so more or different energy will be required to color or bleach the selectively colorable composition than to form the polymeric film or body and colorization or bleaching will be induced at higher intensities than polymerization.
The present invention involves the interaction of a leucobase color former and an oxidizing agent to generate a photosensitive selectively colorable composition. The color former yields a dye cation upon actinic exposure in the presence of an oxidizing agent via electron-transfer process. The The dye cation is then bleached upon further actinic exposure to yield colorless species. The rate of the initial oxidation process can be decreased and controlled by the introduction of at least one electron-withdrawing group (e.g., halogen, N2, COR, COOR, etc., where R is H, hydrocarbon, etc.) to the TAM-H or DAM-H structure. In this case, color formation is delayed allowing one to obtain colorless polymer at low doses, colorize the polymer at an intermediate dose and bleach the color by further irradiation.
Examples of leucobases which yield a colored cation upon exposure to actinic radiation in the presence of an oxidizing agent include thiazine, oxazine and phenazine leucobases as well as triarylmethane leucobases (TAM-X), diarylmethane leucobases (DAM-X) and monoarylmethane leucobases (Arxe2x80x94CR2X) wherein X is H, OH, OR, NR2, N-heterocycle, and R is hydrogen, a straight chain, branched chain or cyclic alkyl group containing 1 to 20 carbon atoms, aryl (e.g., phenyl) or aralkyl (e.g., a phenylalkyl group in which the alkyl moiety contains 1 to 6 carbon atoms) and the like. Preferably, the color former is a triarylmethane or diarylmethane leucobase susceptible to oxidation, with diarylmethane leucobase (DAM-H) being the most preferred color former. Color formers useful in the present invention are preferably stable in acidic media and do not form color on contact with acid. The term xe2x80x9cstable in acidic mediaxe2x80x9d as used herein indicates that the color former will not exhibit more that 0.005% conversion to its colored form in acidic conditions. Stability of the leucobase in acidic media allows it to be used in cationically cured materials for selective color formation.
Examples of triarylmethane leucobase color formers include tris(4-(N,N-dimethylamino) phenyl)methane (Leuco Crystal Violet), tris(4-aminophenyl)methane (Leuco Basic Fuchsin), bis(4-(N,N-dimethylamino)phenyl)pentafluorophenylmethane, bis(4-(N,N-dimethylamino)phenyl) -2-fluorophenylmethane, bis(4-(N,N-dimethylamino)phenyl)-3-fluorophenylmethane, bis(4-(N,N-dimethylamino)phenyl)-2,6-difluorophenylmethane, bis(3-(2-methylindyl))phenylmethane, and the like.
Examples of diarylmethane leucobase color formers include bis(4-aminophenyl)methane, bis(4-(N,N-dimethylamino)phenyl)methane, bis(4-amino-3,5-dimethylphenyl)methane, bis(4-amino-3-chlorophenyl)methane, bis(4-amino-2-chloro-3,5-diethylphenyl)methane, bis(4-aminophenyl)methane, 4-aminophenyl-(4-amino-3-bromophenyl)methane and the like.
Oxidizing agents useful in the present invention include compounds which are electron acceptors capable of oxidizing the leuco dye and generating the colored carbocation. Typical photosensitive oxidizing agents include onium salts such as iodonium, sulfonium and the like, transition metals, iron salts, uranyl salts, etc. used in the absence or presence of an oxidizing species such as hydrogen peroxide. The oxidizing agent, to oxidize the leuco dye, will have a photoreduction potential less than the color former.
Onium salts such as sulfonium or iodonium salts are particularly preferred for use as oxidizing agents in the invention. It is believed that upon photochemical or thermal decomposition, an iodonium salt generates radicals and cations, either or both of which can be used to initiate polymerization, while oxidizing the color precursor which converts the color precursor into its colored form.
Self-coloring photohardenable compositions in accordance with the present invention in their simplest form include a curable compound, an onium salt and a color precursor. In some cases, the compositions may,also include a hydrogen donor, although not essential in the principal embodiments, and for many applications it will also be desirable to include a photoinitiator in the composition.
While triarylsulfonium salts such as triarylsulfonium hexafluoroantimonate or mixtures of triarylsulfonium hexafluoroantimonates and the like are preferred onium salts, other sulfonium salts and iodonium salts are also suitable for use in the invention. Decomposition of triarylsulfonium hexafluoroantimonate can be achieved photochemically. Examples of onium salts useful in the present invention include iodonium salts and sulfonium salts and, more particularly, diaryliodonium hexaflurophosphates, diaryliodonium arsenates and diaryliodonium antimonates. The counter ion of the onium salts is usually a nonnucleophilic semimetal complex such as B(C6F5)4xe2x88x92, Al(C6F5)4xe2x88x92, Ga(C6F5)4xe2x88x92, In(C6F5)4xe2x88x92, Th(C6F5)4xe2x88x92, SbF6xe2x88x92, AsF6xe2x88x92, PF6xe2x88x92, and BF4xe2x88x92. A more complete list of iodonium salts appears in published International Application PCT/US/95/056 13. Representative examples of iodonium salts include salts having the following structures: CnH2nxe2x88x921C6H4I+(C6H5), (CnH2nxe2x88x921C6H4)2I+, (CnH2n+1OC6H4)I+(C6H5) and (CnH2n+1OC6H4)2I+ wherein is preferably 1 and typically 8 to 12 and most preferably, the diaryliodonium salts such as 4,4xe2x80x2-dimethyldiphenyliodonium tetrafluoroborate and (4-octyloxyphenyl) phenyliodonium hexafluoroantimonate (OPPI). Representative examples of sulfonium salts include triarylsulfonium hexafluoroantimonate, triarylsulfonium hexafluorophosphate, triarylsulfonium tetra(perfluoro)phenylgallate, tetra(perfluoro)phenylborate and the like. Examples of particularly preferred onium salts include 1.) OPPI and 2.) a mixture of triarylsulfonium hexafluoroantimonates (UVI-6974 from Union Carbide).
Because decomposition of the onium salt is accompanied by the generation of free radicals and cations, the curable material may be a free radical curable or a cation curable material or a blend of the two. There is a large number of monomers which can be polymerized by cations. These monomers can be classified according to their functionality. They include cyclic ethers, cyclic formals and acetals, vinyl ethers, and epoxy compounds. These monomers can be monofunctional, difunctional and multifunctional. They may also be large molecular weight prepolymers and oligomers. Examples of cationically polymerizable compounds include epoxy compounds, vinyl or allyl monomers, vinyl or allylic prepolymers, vinyl ethers, vinyl ether functional prepolymers, cyclic ethers, cyclic esters, cyclic sulfides, melamineformaldehyde prepolymers, phenol formaldehyde prepolymers, cyclic organosiloxanes, lactams and lactones, cyclic acetals and epoxy functional silicone oligomers.
Epoxy monomers are the most important class of cationic polymerizable substrates. These materials are readily available and the resulting cured polymers possess excellent dimensional and thermal stability as well as superior mechanical strength and chemical resistance. They are widely used in the coating, painting and adhesives industry. Examples of cationically polymerizable epoxy compounds described in the literature include any monomeric, dimeric or oligomeric or polymeric epoxy material containing one or a plurality of epoxy functional groups. Examples of polymerizable epoxy compounds include bisphenol-A-diglycidyl ether, trimethylene oxide, 1,3-dioxolane, 3,4-epoxycyclohexylmethyl-3xe2x80x2,4xe2x80x2-epoxycyclohexyl carboxylate, phenyl glycidyl ether, 4-vinylcyclohexene dioxide, limonene dioxide, cycloaliphatic epoxides such as 1,2-cyclohexene oxide, epichlorohydrin, glycidyl acrylate, glycidyl methacrylate, styrene oxide, allyl glycidyl ether, etc. Resins which result from the reaction of bisphenol A (4,4-isopropylidenediphenol) and epichlorohydrin, or from the reaction of low molecular weight phenol-formaldehyde resins (Novolak resins) with epichlorohydrin have been used alone or in combination with an epoxy containing compound. In addition, polymerizable epoxy compounds include polymeric materials containing terminal or pendant epoxy groups. Examples of these compounds are vinyl copolymers containing glycidyl acrylate or methacrylate as one of the comonomers. Other classes of epoxy containing polymers amenable to cure have also been described in the literature and include epoxy-siloxane resins, epoxy-polyurethanes and epoxy-polyesters. Such polymers usually have epoxy functional groups at the ends of their chains. Epoxy-siloxane resins and the method for making them are more particularly shown by E. P. Plueddemann and G. Ganger, J. Am. Chem. Soc. 81 632-5 (1959), and in Crivello et al., Proceeding ACS, PMSE, 60, 217 (1989). As described in the literature, epoxy resins can also be modified in a number of standard ways such as reactions with amines, carboxylic acids, thiols, phenols, alcohols, etc. as shown in U.S. Pat. Nos. 2,935,488; 3,235,620; 3,369,055; 3,379,653; 3,398,211; 3,403,199; 3,563,850; 3,567,797; 3,677,995, etc. Further examples of epoxy resins are shown in the Encyclopedia of Polymer Science and Technology, Vol. 6, 1967, Interscience Publishers, New York, pp. 209-271.
Examples of vinyl or allyl organic monomers which have been used in the literature in the practice of the cationic polymerization include, for example, styrene, vinyl acetamide, methyl styrene, isobutyl vinyl ether, n-octyl vinylether, acrolein, 1-diphenylethylene. R-pinene; vinyl arenes such as 4-vinyl biphenyl, 1-vinyl pyrene, 2-vinyl fluorene, acenapthylene, 1 and 2-vinyl napthylene; 9-vinyl carbazole, vinyl pyrrolidone, 3-methyl-1-butene; vinyl cycloaliphatics such as vinylcyclohexane, vinylcyclopropane, 1-phenyvinylcyclopropane; dienes such as isobutylene, isoprene, butadiene, 1,4-pentadiene, 2-chloroethyl vinyl ether, etc. Some of the vinyl organic prepolymers which have been described are, for example, CH2xe2x95x90CHxe2x80x94Oxe2x80x94(CH2O)nxe2x80x94CHxe2x95x90CH2, where n is a positive integer having a value up to about 1000 or higher; multi-functional vinylethers, such as 1,2,3-propane trivinyl ether, trimetheylolpropane trivinyl ether, polyethyleneglycol divinylether (PEGDVE), triethyleneglycol divinyl ether (TEGDVE), vinyl ether-polyurethane, vinyl ether-epoxy, vinyl ether-polyester, vinyl ether-polyether and other vinyl ether prepolymers such as 1,4-cyclohexane dimethanol-divinylether, commercially available from GAF and others, and low molecular weight polybutadiene having a viscosity of from 200 to 10,000 centipoises at 25xc2x0 C., etc.
A further category of cationically polymerizable materials are cyclic ethers which are convertible to thermoplastics. Included by such cyclic ethers are, for example, oxetanes such as 3,3-bis-chloromethyloxetane alkoxyoxetanes as shown by U.S. Pat. No. 3,673,216; oxolanes such as tetrahydrofuran, oxepanes, oxygen containing spiro compounds, trioxane, dioxolane, etc. In addition to cyclic ethers, there are also included cyclic esters such as lactones, for example, propiolactone, cyclicamines, such as 1,3,3-trimethylazetidine and cyclic organosiloxanes, for example. Examples of cyclic organosiloxanes include hexamethyl trisiloxane, octamethyl tetrasiloxane, etc. Cyclic acetals may also be used as the cationic polymerizable material. Examples of epoxy functional silicone oligomers are commercially available from General Electric and are described in ACS PMSE Proceeding 1989, Vol. 60, pp. 217, 222.
Because the photoinitiator generates both free radicals and cations, it is possible to utilize a combination of free radical polymerizable and cationic polymerizable monomers. Examples of free radical polymerizable monomers include both monomers having one or more ethylenically unsaturated groups, such as vinyl or allyl groups, and polymers having terminal or pendant ethylenic unsaturation. Such compounds are well known in the art and include acrylic and methacrylic esters of polyhydric alcohols such as trimethylolpropane, pentaerythritol and the like, and acrylate or methacrylate terminated epoxy resins, acrylate or methacrylate terminated polyesters, etc. Representative examples include ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropane triacrylate (TMPTA), pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, dipentaerythritol hydroxypentacrylate (DPHPA), hexanediol-1, 6-dimethacrylate, and diethyleneglycol dimethacrylate.
Examples of materials which are both cationically and free radically cured include glycidyl methacrylates, epoxy acrylates, acrylated melamine formaldehyde and epoxidized siloxanes. The simultaneous utilization of a cationically and free radical curable system enables rapid curing to be accomplished and provides a wide latitude in the design of product performance. For example, when a solution of acrylate and epoxy acrylate is used as the dual curable composition, film properties ranging from flexible to rigid can be produced and desired adhesive characteristics can be produced by selection of designed ratios of functional groups. The epoxy functionality provides high temperature resistance, excellent adhesion and reduced oxygen sensitivity whereas the acrylate functionality provides rapid curing speed, excellent weatherability, flexibility and desirable viscosity. Other examples of dual curable systems will be envisioned and appreciated by those skilled in the art. It has been found that a mixture of an acrylate and an epoxy compound is particularly desirable for use herein.
In accordance with one embodiment of the present invention, a photoinitiator is included in the self coloring photohardenable composition. Some typical examples of photoinitiators which are expected to be useful in the present invention are xcex1-alkoxy phenyl ketones, O-acylated-xcex1-oximinoketones, polycyclic quinones, benzophenones and substituted benzophenones, xanthones, thioxanthones, halogenated compounds such as chlorosulfonyl and chloromethyl polynuclear aromatic compounds, chlorosulfonyl and chloromethyl heterocyclic compounds, chlorosulfonyl and chloromethyl benzophenones and fluorenones, haloalkanes, xcex1-halo-xcex1-phenylacetophenones, halogenated paraffins (e.g., brominated or chlorinated paraffin) and benzoin alkyl ethers. A wide range of xanthene or fluorone dyes may be used as photoinitiators in accordance with the invention. Some examples include Methylene Blue, rhodamine B, Rose Bengal, 3-hydroxy-2,4,5,7-tetraiodo-6-fluorone, 5,7-diiodo-3-butoxy-6-fluorone, erythrosin B, Eosin B, ethyl erythrosin, Acridine Orange, 6xe2x80x2-acetyl-4xe2x80x2,5xe2x80x2,6xe2x80x2,7xe2x80x2-tetraiodofluorescein (RBAX), and the fluorones disclosed in U.S. Pat. No. 5,451,343.
For some applications it may be desirable to include a hydrogen donor in the compositions of the invention. Useful hydrogen donors can be selected from among those known in the art and, more particularly, from known hydrogen donating coinitiators. Non-nucleophilic amines such as aromatic amines of low basicity are particularly useful in the invention. The relative efficiency of the hydrogen donor in cationic polymerization not only depends on the efficiency of radical generation, but also on the efficiency of the oxidation of the radicals to cations as well as on the efficiency of the cation to initiate the cationic polymerization. The hydrogen donor must have a low basicity and low nucleophilicity. If the hydrogen donor is too basic, it will deactivate the cationic center responsible for initiation. Only aromatic amines with a hydrogens are capable of initiating ring opening polymerization of cyclohexene oxide. Aliphatic amines, aromatic amines without xcex1-hydrogens and non-amine hydrogen donors are incapable of the initiation with cyclohexene oxide.
Representative examples of N,N-dialkylanilines useful in the present invention are 4-cyano-N,N-dimethylaniline, 4-acetyl-N,N-dimethylaniline, 4-bromo-N,N-dimethylaniline, 4-methyl-N,N-dimethylaniline, 4-ethoxy-N N-dimethylaniline, N,N-dimethylthioanicidine, 4-amino-N,N-dimethylaniline, 3-hydroxy-N,N-dimethylaniline, N,N,Nxe2x80x2Nxe2x80x2-tetramethyl-1,4-dianiline, 4-acetamido-N,N-dimethylaniline, 2,6-diethyl-N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline(PMA) p-t-butyl -N,N-dimethylaniline and N,N-dimethyl-2,6-diisopropyl aniline. Also useful as hydrogen donors are N-phenylglycine and N,N-dimethyltoluidine. However, the invention is not limited to the use of amines or aromatic amines as hydrogen donors. Other compounds present in the composition may be capable of functioning as a hydrogen donor. For example, many monomers are capable of acting as hydrogen donors and compositions containing these compounds may be used effectively with or without amines. Specific examples of such monomers include certain cycloaliphatic epoxides.
Solvents may be necessary to dissolve components of the system including the photoinitiator, the color precursor, etc., if they are not sufficiently soluble in the monomer. Some examples of useful solvents are ethyl acetate, etc. Other useful solvents can be identified readily.
The nature of the monomer or polymerizable material, the amount of the color precursor and onium salt in curable self-coloring compositions in accordance with the present invention will vary with the particular use of the compositions, the emission characteristics of the exposure sources, the development procedures, the physical properties desired in the polymerized product and other factors. With this understanding, compositions in accordance with the invention will generally fall within the following compositional ranges in parts by weight (based on 100 parts total).
Compositions in accordance with the invention more typically are anticipated to have the following formulation:
Preferably, the color formers are present in an amount sufficient to provide a contrast ratio of at least 1.5, more preferably at least 10, or provide a contrast ratio of less than 0.7 in the case of reversed contrast. The term xe2x80x9ccontrast ratioxe2x80x9d means the ratio of absorbance maximum values at two doses. These doses are the largest dose and the dose at which the polymer is formed unless specified otherwise. As used herein contrast ratio refers to the absorbance of the colored polymeric film or body at the high irradiation dose divided by the absorbance at the low dose at the specified wavelength. Contrast ratio is a function of a number of variables including, but not limited to, the light source, irradiation dosage, curable compound, photoinitiator and color formers.
The number of color formers, type of color formers, the concentration of the color formers, the interaction between the different color formers and the relative concentrations of the color formers influence the contrast ratio.
The compositions of the present invention are useful in the following applications: creating color contrast in printing plates such as in flexographic plates, other proofing and identification purposes, end of line manufacturing identification, fraud protection, selective imagewise colorization of a wire or other plastic objects, color printing of relief and 3D images with various light sources, and the like. The photohardenable composition of the invention may also be advantageous for use in the three dimensional modeling process taught in U.S. Pat. No. 4,575,330 to Hull and commonly assigned U.S. Pat. No. 5,514,519, the latter being hereby incorporated by reference.
Irradiation of resins consisting of monomers, preferably acrylates or epoxides and most preferably a mixture of acrylates and epoxides, a leucobase color former and a sulfonium salt can result in selectively colored films in which the polymerization process and the color formation occur simultaneously. Alternatively, the polymerization process can be conducted prior to the color formation.
In a preferred embodiment of the present invention, a photopolymerizable composition comprising a cationically polymerizable epoxide, a triarylsulfonium salt photoinitiator, an acrylate and a free radical photoinitiator is polymerized in the presence of a diarylmethane leucobase color former (DAMH). Color formation proceeds according to the following mechanisms:
DAMH+Ox+hxcexdDAM+xe2x80x83xe2x80x83Mechanism 1
The color of the polymeric body at low doses is solely determined by DAM+. At high doses this cation is partially or completely bleached (Mechanism 2), thus, the polymer body has no or little color.
DAM++hxcexdbleaching products (colorless)xe2x80x83xe2x80x83Mechanism 2
In another embodiment of the present invention, the oxidation process can alternatively be inhibited significantly by the introduction of at least one electron-withdrawing group (halogen, NO2, COR, COOR, etc., where R is H or a hydrocarbon group) to the TAM-H or DAM-H, preferably DAM-H structure. In this case, the color formation is delayed allowing one to obtain colorless polymer at low doses, colorize it at higher doses and bleach the color at even higher doses.
Although the present invention has been primarily described by reference to polymerizable compositions, the invention is not so limited. The selectively colorable compositions can be liquids or solids which form color on exposure to actinic radiation and the color so formed can be bleached by further irradiation.

Selectively colorable polymerizable compositions


Flame retardant hot melt adhesives include ethylene vinyl acetate having grafted thereon a ring-halogenated styrene. The compositions may also include homopolymers of the styrene monomer of equivalents, as well as non-halogenated ethylene vinyl acetate. Tackifying agents, waxes, anti-oxidants and other additives may also be included.

1. Field of the Invention
The present invention relates to the field of composite useful in the manufacture of hot melt adhesives and to the adhesive compositions themselves, and particularly to the preparation of flame retardant hot melt adhesives containing ethylene vinyl acetate.
2. Description of the Prior Art
A hot melt adhesive is generally manufactured from a mixture of three components: a thermoplastic resin capable of providing cohesion of the mixture, a petroleum resin having a tackifying effect, and a paraffin or a microcrystalline polymeric wax capable of adapting the viscosity of the mixture to the processing and use conditions of the adhesive. In choosing the thermoplastic resin part of the mixture, good properties are sought in respect to heat stability and adhesiveness. The thermoplastic resins commonly used in compositions for the manufacture of hot melt adhesives have included copolymers of ethylene and vinyl esters, particularly vinyl acetate, or copolymers of ethylene and alkyl acrylates, particularly ethyl acrylate and butyl acrylate.
A typical hot melt adhesive formulation is described in U.S. Pat. No. 4,325,853, issued to Acharya et al. on Apr. 20, 1982. This patent indicates that a typical adhesive comprises, for example, ethylene copolymer, a tackifier and a wax. The Acharya patent is directed to the particular use of alkenyl succinic anhydride in combination with ethylene copolymer and a tackifying resin. It is indicated that wax-like materials and anti-oxidants may also be used. Among the ethylene copolymers mentioned are ones with vinyl acetate or with acrylic and methacrylic acid.
A general form of hot melt adhesive is also described in U.S. Pat. No. 4,404,299, issued to Decroix on Sep. 13, 1983. The Decroix patent indicates the adhesive to conventionally include a thermoplastic resin, a tackifying resin, and a paraffin or other wax-like substance for modifying the melt viscosity. Particularly described in the Decroix patent is the use of a terpolymer of ethylene and minor parts of alkyl acrylate or methacrylate and of maleic anhydride.
While ethylene vinyl acetate (EVA) has been found to be well suited to use in hot melt adhesives, there has remained a desire to improve the flame retardancy of EVA without adversely affecting the other desirable properties of EVA. Approaches to this problem have included the modification of EVA directly or the addition of flame retardants into the overall adhesive formulation.
Hot melt adhesive formulations can be made flame retardant by the addition of halogenated liquid and/or solid additives. However, liquid additives weaken the adhesive bond strengths by dilution and plasticization of the adhesive formulation. On the other hand, solid additives act as fillers, and can result in settling and lower tensile strengths. Present adhesive dispensing systems are not generally equipped with stirrers, and solid insoluble flame retardant additives which settle out of the adhesive can clog feed lines.
U.S. Pat. No. 3,034,939, issued to Newkirk, et al. on May 15, 1962, discusses fire extinguishing properties for a hot melt adhesive composition containing chlorinated biphenyls and/or chlorinated paraffins as flame retardants. The use of the former material is now EPA regulated due to PCB contamination problems. The latter material is subject to dehydrochlorination if allowed to stand at the 270.degree.-350.degree. F. temperature required for use. Additionally, antimony trioxide and calcium carbonate (which tend to settle out) are required. There is no adhesive data in the Newkirk, et al. patent.
Other commercial flame retardants, such as decabromodiphenyl oxide (DDPO) are also used in flame retardant hot melt adhesives, as described in U.S. Pat. No. 4,727,107, issued to McConnell, et al. on Feb. 23, 1988. DDPO is an insoluble solid melting at 300.degree.-315.degree. C., which acts as a filler and can settle out of the adhesive formulation. The McConnell patent claims the use of decabromodiphenyl ether in flame retardant hot melt adhesives for polyurethane foams and fabrics. The use of antimony oxide is also claimed. These materials will settle out of the adhesive mixture. Also, formulating the adhesive is cumbersome due to the pre-melting and mixing of the flame retardant and antimony oxide with polyester to form a concentrate which is then back-added to the base polyester for application. No adhesive data is given in the McConnell patent.
The graft ethylene vinyl acetate polymers used in the present invention do not suffer the drawbacks of having insoluble flame retardants which act as fillers, increase melt viscosity, and require the use of solid antimony synergists or other flame retardant enhancing agents. Since the grafts are polymeric and compatible in the adhesive formulation, they do not perform like liquid flame retardants which can weaken and migrate from adhesive bonds.

Flame retardant hot melt adhesive compositions


A linear ignition system for a metal-sheathed linear explosive including in one embodiment the ends of two metal-sheathed linear explosives are connected by a non-electrically conductive sleeve leaving a gap between the ends, and a Pyrofuze(copyright) bridge connects the metal-sheath of one end to the metal sheath of the other end. Electrical contacts are made to the two metal sheaths and application of current to the electrical contacts ignites the Pyrofuze(copyright) bridge and the linear explosives. Embodiments can also include an explosive mixture in the gap, using a hotwire bridge, or including booster increments for initiating detonating explosives. The linear ignition systems offer robust, easy-to-install linear explosive devices for applications in automotive, commercial or military aircraft safety systems, other military and aerospace applications, and commercial blasting.

1. Field of the Invention
The present invention relates to the field of explosives, in particular to igniting devices, and more particularly to igniting devices for metal-sheathed linear explosives and pyrotechnics.
2. Description of the Related Art
Linear explosive and pyrotechnic products, such as Linear Shaped Charge (LSC), Mild Detonating Cord (MDC) and Rapid Deflagrating Cord (RDC) are typically initiated using a separate, distinct, electrically initiated ignition device to provide either a brisant, pyrotechnic or high order shock stimulus for the linear explosive material. Of particular interest are linear shaped charge, mild detonating cord and rapid deflagrating cord devices contained within a metal sheath. Linear shaped charge devices having an explosive wrapped in a continuous metallic sheath are commonly used for severing materials. Sheathed mild detonating cord is used to transfer an explosive stimulus in a contained manner and may be used to instantaneously shear certain structures. These products have potential applications in a wide range of applications such as automotive and commercial aircraft safety systems, aircrew escape and safety systems, military weapon system ignition, event sequencing and submunition dispensing, launch vehicle event sequencing, and various commercial blasting and oilfield applications.
Generally, in such systems, the linear pyrotechnic or explosive device is provided separately from, and must be mounted and installed with. a separate initiation (ignition) device. However, the use of a separate ignition device increases the cost and complexity of the use of these systems. These devices generally must be installed with an adapter to the linear pyrotechnic device, and the installation of the separate ignition device requires labor, adding to the cost. Moreover. with separate ignition devices, there is often a possibility for a mistake in installation, such as failure to remove the safety cap. For failsafe systems, testing of the installed ignition device may also be difficult.
Moreover, conventional initiators or detonators have some risk of accidental initiation due to electrostatic discharge (ESD) or electromagnetic radiation. which is an important safety and handling issue. In addition, most conventional initiation devices have a lifetime which may be considerably shorter than that of the linear pyrotechnic or explosive, therefore limiting the life of the installed system.
Examples of the conventional art of initiating devices are seen in the following U.S. Patents. U.S. Pat. 4,070,970, to Scamaton, entitled ELECTRO-EXPLOSIVE IGNITERS, describes an electrically initiated igniter having a layer of pyrotechnic mixture packed between two initiating electrodes. This is a separate device from the actual explosive, and is for non-brisant initiation; a detonator capsule must be attached for brisant ignition.
U.S. Pat. No. 4,312,271, to Day et al., entitled DELAY DETONATION DEVICE, describes a delay detonator device having a bridge wire which ignites a delay charge.
U.S. Patent No. 4,422,381, to Barrett. entitled IGNITER WITH A STATIC DISCHARGE ELEMENT AND FERRITE SLEEVE, describes an electroexplosive device with a cylindrical electrically conductive metal casing which is open at one end. and which has a bridge element and lead wires.
U.S. Patent No. 4,976,200, to Benson et al., entitled TUNGSTEN BRIDGE FOR THE LOW ENERGY INITIATION OF EXPLOSIVE AND ENERGETIC MATERIALS. describes a device fabricated on a silicon-on-sapphire substrate.
U.S. Patent No. 5,036.769, to Schaff et al., entitled PYROFUZE PIN FOR ORDNANCE ACTIVATION, describes a device designed to avoid accidental arming of ordnance, and having a Pyrofuize pin, a connecting ignitor transfer charge, ignitor and electrical terminals in a weatherproof housing.
U.S. Patent No. 5,225,621, to Kannengiesser et al., entitled PROCESS FOR PRODUCING A
JACKETED FUSE AND FUSE PRODUCT, describes a fuse with a jacket produced from a shrinkable hose which is shrink-fitted onto unfinished cord containing an explosive.
U.S. Patent No. 5,392,713, to Brown et al., entitled SHOCK INSENSITIVE INITIATING DEICES, describes a device which has a thin elongated metal casing containing a quantity of hydrated metal picrate and an ignition means which may be an electric match.
Based on our reading of the art, then, we have decided that what is needed is an improved system for initiation of explosive and pyrotechnic devices.
It is therefore an object of the present invention to provide an improved ignition device for metal-sheathed linear explosives and pyrotechnics.
It is a further object of the invention to provide a less complex ignition device.
A still further object of the invention is to provide a linear initiation system which is easier to install.
A yet further object of the invention is to provide a linear initiation system which is less expensive.
Another object of the invention is to provide a linear initiation system which has a longer service life.
Yet another object of the invention is to provide a linear initiation system which is less susceptible to electrostatic discharge and electromagnetic radiation.
Still another object of the invention is to provide a linear initiation system which is more reliable.
These objects are achieved in the linear ignition system of the present invention. One embodiment of the present invention includes two metal-sheathed linear explosives, the ends of which are connected by a non-electrically conducting sleeve leaving a gap between the ends. Bridging this gap is a bridge made from an exothermic metal composition, and electrical contacts are made to each of the metal sheaths of the two linear explosives. Upon application of voltage, current flows through the sheaths, ignites the bridge, when in turn ignites the linear explosive. Here, the term xe2x80x9cexplosivexe2x80x9d is used generally, and covers high explosives which detonate, low explosives which are classed as mild or rapid deflagrating materials, as well as pyrotechnics.
Additional embodiments are presented in which booster increments are included placed against each end of the linear explosive to allow initiation of explosives requiring detonation. Embodiments are described in which an explosive material is included in the gap, and in some embodiments, a hotwire bridge is used instead of the exothermic metal composition.
In another embodiment. the ends of two metal-sheathed linear explosives are connected by Is a non-conducting sleeve, leaving an unbridged air gap between the ends. Here, application of sufficient voltage across the metal sheaths leads to a spark in the gap, causing ignition. In another embodiment, the gap contains an explosive material. It is also possible to have booster increments on the end of each linear explosive and to provide electrical contacts around the booster increments the gap formed between the booster increments. In this embodiment, the spark would occur in the gap between the booster increments and ignite the booster increments.
In another embodiment of the invention, a single metal-sheathed linear explosive is covered at one end by an insulating sleeve and a metal end cap over the sleeve, forming a gap between the end of the linear explosive and the inside end of the end cap. A bridge made of an exothermic material extends across the gap within the end cap from the metal sheath to the metal end cap. Electrical contacts are made to the metal end cap and the metal sheath for ignition of the bridge to ignite the linear explosive. Additional embodiments having the end cap are presented in which a booster increments is placed against each the end of the linear explosive, in which an explosive material is included in the gap, or in which a hotwire bridge is used instead of the exothermic metal composition.
Embodiments are also described in which no bridge is present in the gap between the end cap and the end of the linear pyrotechnic, and in which the gap series as a spark gap. Here, a booster element or an explosive mixture in the gap may also be provided.


The present invention provides an absorbent article having a silhouette that includes a first portion and a second portion, wherein the second portion is in opposite relation to the first portion, and a pair of opposed longitudinally extending sides connecting the first portion to the second portion. The absorbent article also contains a layered portion with a substantially transparent cover layer that absorbs fluid, a substantially transparent backsheet layer, and an optional absorbent core, which may be substantially transparent. At least one flap may optionally extend laterally from a longitudinally extending side.

This invention relates to an absorbent article, such as pantyliners. More particularly, the present invention relates to discrete pantyliners for use with conventional and thong-type underwear. The invention includes means for attaching the absorbent article to underwear such that the attachment means are not discernible through the clothing of the user.
Currently, absorbent articles for sanitary protection, such as, pantyliners, sanitary napkins, and incontinence pads, must fit a variety of individual body shapes and sizes. In particular, women have an almost infinite variety of body shapes and muscle tone in the upper thigh region. A product that offers superior comfort, fit, and protection for one woman may be deficient for another woman due to her body shape and muscle tone.
The availability of different types of underwear also affects the choice of absorbent articles for sanitary protection. For example, conventional pantyliners and napkins are typically designed to be used with underwear having a full sized crotch portion, e.g., briefs and bikinis. However, such conventional pantyliners and napkins attach poorly to underwear having an abbreviated crotch portion, e.g., thong or G-string, which have a substantially narrower posterior end compared to the anterior end. As a result, many women purchase multiple types of sanitary protection depending on the underwear they choose to wear.
One problem with pantyliners, especially those for use with thong underwear, is their ability to be secured to such underwear and to stay in place. For example, there is little surface area of fabric at the narrow posterior end of such pantyliners for such pantyliners to attach. Additionally, the area between the buttocks is sensitive and subject to a high degree of movement.
Attaching a pantyliner to underwear, including thong, often includes at least one flap, tab or wing that extends laterally from a side edge of the liner that wraps around to the outside of the underwear fabric and attaches thereto. As used herein, xe2x80x9cflap,xe2x80x9d xe2x80x9ctab,xe2x80x9d and xe2x80x9cwing,xe2x80x9d whether plural or singular, are interchangeable and shall have the same meaning. Attachment of the flaps is typically accomplished by having an adhesive on the side of the flaps that face the outer underwear fabric.
Typically, absorbent articles used as sanitary protection are white. Because the materials, e.g., fibers and polymers, used to make the components, e.g., cover, absorbent core and barrier, of such absorbent articles often do not have the desired whiteness, pigments, dyes, or color imparting materials, such as, titanium dioxide, are added to such materials to produce the desired whiteness. However, for example, a cover and backsheet produced from such pigmented materials may make the flaps highly visible, thereby reducing discretion.
Accordingly, the need exists for a pantyliner that will attach securely to thong underwear and stay there, so as not to be discernible, especially through clothing. There is also a need for a pantyliner having a conventional silhouette that provides discretion because it is substantially transparent.
The present invention provides an absorbent article having a silhouette that includes a first portion and a second portion, wherein the second portion is in opposite relation to the first portion, and a pair of opposed longitudinally extending sides connecting the first portion to the second portion. The absorbent article also contains a layered portion with a substantially transparent cover layer that absorbs fluid, a substantially transparent backsheet layer, and an optional absorbent core, which may be substantially transparent. At least one flap may optionally extend laterally from a longitudinally extending side.
The absorbent articles of this invention, include, but are not limited to, sanitary napkins, pantyliners, incontinence devices, wound care articles, e.g., surgical dressings and adhesive bandages, shoe liners and the like.
As is well known to those skilled in the art, absorbent articles that are worn externally generally have a layered construction with a body-facing surface that is oriented to face the wearer during use and a garment-facing surface oriented in the opposite direction from the body-facing surface. Typically such articles have a liquid previous cover on the body-facing surface of the article, an absorbent core and a backsheet on the garment-facing surface of the article. The absorbent core is interposed between the cover and the backsheet. The cover and the backsheet encase all components of the article. The cover and the backsheet may be joined or sealed to each other along their peripheral edge using any method known in the art.
Flaps, also known as wings, tabs and the like, are generally flexible and configured to be folded over the edges of the underwear so that the flaps anchor or secure the absorbent article to the underwear.
According to the present invention, the cover and backsheet are made from pigment-free materials. The cover, backsheet or a combination thereof may be used to form flap, thereby creating flaps that are formed from pigment-free materials. In a preferred embodiment, the cover and backsheet are substantially coextensive and are joined together about the periphery of the absorbent article. This results in a periphery, including any flap(s), that is substantially transparent.
As used herein, substantially transparent refers to those materials having a transparency of between about 60 to 100 percent light transmittance. Essential criteria of transparency are total transmittance, haze and clarity. Total transmittance is the ratio of total transmitted light to incident light. It is reduced by reflectance and absorbance. Haze is the percentage is the percentage of transmitted light that deviates from the incident beam by more than about 2.5 degrees on average. Clarity can be evaluated at angles of less than about 2.5 degrees.
In accordance with an embodiment of the present invention, there is provided a novel absorbent article, having a pigment-free body-facing fluid permeable cover sheet, a pigment-free fluid impermeable backsheet, which in the case of sanitary absorbent articles, face the users garment when in use.
In another embodiment of the present invention, there is provided a novel absorbent article, having a pigment-free body-facing fluid permeable cover sheet, a pigment-free fluid impermeable backsheet, which in the case of sanitary absorbent articles, face the users garment when in use, and a pigment-free absorbent core between the cover sheet and the backsheet.
In an alternate embodiment of the present invention, the absorbent article includes at least one flap extending laterally outward that is substantially transparent. The flap being made from the backsheet, the cover, or both.
The pigment-free liquid permeable cover sheet of an absorbent article of the present invention may be formed from any fluid previous material that is comfortable against the skin and permits fluid to penetrate to the absorbent core. The cover should retain little or no fluid in its structure in order to provide a relatively dry surface next to the skin. The cover may be a fibrous fabric made of fibers, including bicomponent fibers, or filaments of polymers, such as polyethylene, polypropylene, polyester, or cellulose. Alternatively, the cover may be formed from an apertured film, plastic nets, webs and the like. Any of these materials may be used provided that the cover, especially the outer edge portion be free of any pigment and be substantially transparent. The cover may be, for example, a 9 gsm polypropylene having code SB-PTE 09 available from Shalag, Upper Tieberias, Israel.
In a preferred embodiment, the cover is a pigment-free, non-woven fabric formed from an interconnected network thermoplastic polymer fibers, at least a portion of the non-woven fabric having a three-dimensional thickness profile.
The optional absorbent core of an absorbent article of the present invention can be a fluffy batt cut from a relatively loose web of non-woven fibers having a relatively high absorptive capacity. While the absorbent core can have any shape or silhouette, it usually has an asymmetric configuration. The absorbent core is usually smaller than the backing sheet and the cover. The absorbent core may also be a fibrous batt having an integral densified layer. In such a case, the absorbent core is positioned on the backing sheet of the absorbent article so that the densified layer adjoins the backing sheet. The densified layer has relatively higher wettability and liquid retentivity than the rest of the aforesaid batt and usually is formed by slightly moistening one surface of the batt and thereafter compressing the moistened surface.
An absorbent core may contain any material that absorbs bodily secretions including, but not limited to pulp, polymeric fibers and filaments, sphagnum moss, natural fibers, superabsorbent polymers (including fibers, particulate material and foams), absorbent foams, and other such absorbent materials. The core may optionally be any substrate, e.g., tissue, woven, nonwoven, netted material, lace, foam, and apertured polymeric film. This substrate may be treated with a treating solution of polyacrylic acid oligomers that are crosslinked onto the substrate via removal of the solvent. Additionally, a platicizing agent, such as, e.g., glycerine, carbowax, PEG 400-900, etc. may be included in the treating solution in an amount of about up to 20%. Such solutions of polyacrylic acid oligomers include, but are limited to, FULLATEX, (code PD-8081H from HB Fuller Co., St. Paul, Minn,), which is a solution having 80% water and 20% polyacrylic acid oligomer. Crosslinking agents that may be used include, but are not limited to, ammonium zirconyl carbonate (available as 5% BACOTE 20 from Magnesium Electron, Flemington, N.J), azirdine (available as NEOCRYL from Zeneca Resins, Wilmington, Del.). One of the advantages of such treated absorbent cores is that they are more transparent than other cores, e.g., those made of pulp. In addition, such treated cores may become more transparent upon the addition of liquid.
The absorbent core may be formed from cellulosic fibers and superabsorbent polymer particles. The absorbent core may also include additional materials such as odor control material, wetness indicator material, materials for administering or delivering medicaments, such as encapsulated medicaments, and materials for maintaining skin moisture, such as encapsulated moisturizers.
The backsheet of an absorbent article of the present invention may be of any flexible, pigment-free material that prevents the transfer of fluid through it, but does not necessarily prevent the passages of vapors. Backsheets that are previous to vapor are known as breathable backsheets. In general, these backsheets are intended to allow the passage of vapor or water molecules through them while retarding, at least to a degree, the passage of fluid. Monolithic film technology provides materials that can be used to form sheets that allow vapor transmission, but are relatively impervious to liquids. Commonly used materials are segmented block copolymers, polyvinyl alcohol, polyurethane, cellulosics and blends thereof. Other materials that may be used as impermeable barriers may be chosen from films of polypropylene, polyethylene, polyesters, polyamides, polyethylene vinyl acetate, polyvinyl chloride, and polyvinylidene chloride. Co-extruded and laminated to combinations of the foregoing, wherein such combinations are permitted by the chemical and physical properties of the film, may be used. Fluid impermeable nonreticulated foams may also be used. Films that are fluid barriers, but permit vapors to transpire, i.e., xe2x80x9cbreathable films,xe2x80x9d may also be used. These include in particular, monolithic, porous or microporous films, as previously described. The vapors most commonly used to demonstrate a film""s breathability are water vapor, sometimes referred to as moisture vapor, and oxygen.
A suitable backsheet material can be a pigment-free monolithic film made from segmented block copolymers where one block is hydrophilic and the other block hydrophobic in nature, alternative materials for monolithic films are polyvinyl alcohol, polyurethane, cellulosics and blends thereof In a preferred embodiment, the backsheet is made from a pigment-free and filler-free monolithic sheet made from segmented block copolymers. For example, the back sheet may be 0.8 mil, polypropylene film such as that supplied by the Edison Plastic Co. (Newport News, Va.) (Code XP-766-B), a film from Filmtech. Corp. (Lehigh Valley, Pa.), or it may be a polyethylene film available from Tredegar Film Products (Richmond, Va.) (Code X28480). Suitable monolithic films are marketed by Atochem under the trade name Pebax, and by Du Pont under the trade name Hytrel.
The backsheet may be fixed or otherwise adhered or secured to the surface of the absorbent core overall or in discrete zones of attachment. The backsheet may be adhered to the cover in an overlapping configuration, for example, parallel to the No sides of the absorbent structure, parallel to the bottom of the absorbent article or in a flange seal extending from the sides of the absorbent structure. When the cover and backsheet are adhered to each other in a flange seal, the cover may additionally be wrapped around the flange seal about the cover; or the backsheet may additionally be wrapped around the flange seal about the cover.
The absorbent article may optionally have a multi-layered structure that may additionally contain a pigment-free transfer layer, which is a low density fluid accepting and fluid releasing layer, that is usually located between the cover and the absorbent core. The transfer layer may be made of relatively less hydrophilic materials and structures than is contained in the absorbent core, such as of webs of polypropylene or polyester nonwovens. Transfer layers may also be made of synthetic fibers, such as polyethylene, polypropylene, polylactic acid, polyester, polyacrylonitrile, polyamide, bicomponent, and mixtures thereof Such highloft webs may be bonded with chemical binders or by thermal means such as by through-air bonding.
The layers of the article may be attached or adhered to one another to form a cohesive unit to enhance the article""s stability. Such attachment or adherence may be by any known means, including, for example, adhesive, ultrasonics, co-embossing, thermobonding, mechanical bonding, and the like. However, it is preferred that the adhesive is colorless, e.g., a Gardner color of about 3 or less, and does not inhibit the light transmission, vapor transmission, or breathability of the backsheet. In the case of a pantyliner, a pigment-free construction adhesive is preferred to be present between the cover and the absorbent core and also present between the absorbent core and the backsheet. The construction adhesive serves to hold the layers together and to minimize deformation during use. The adhesive can be applied as either a thin porous film or in a random spray, in a controlled spiral pattern, or in any other application pattern. See, for example, U.S. Pat. Nos. 5,462,538; 5,681,305 and 5,885,681.
The absorbent article, in the case of a pantyliner, may be applied to the crotch of underpants by placing the backsheet of the absorbent article against the inside of the crotch of the underpants. Pressure sensitive adhesive that is colorless or pigment-free may be applied to the outer surface backsheet of the absorbent article to help maintain it in place. As used herein, the term xe2x80x9cpressure-sensitive adhesivexe2x80x9d refers to any pigment-free releasable adhesive having a Gardner color of about 3 or less or releasable tenacious means that does not substantially decrease light transmissibility. Suitable pressure sensitive adhesives include, for example, water-based adhesives such as acrylate adhesives. Alternatively, the adhesive may be a rapid setting thermoplastic xe2x80x9chot meltxe2x80x9d rubber adhesive or two-sided adhesive tape.
A paper release strip that has been coated on one side, may be applied to protect the adhesive on the backsheet prior to use. The coating on the release paper, for example, silicone, reduces adherence of the coated side of the release to the backsheet adhesive. The release strip can be formed from any suitable sheet-like material that, when coated, adheres with sufficient tenacity to the adhesive to remain in place prior to use, but can be readily removed when the absorbent article prior to placement on the wearer""s underpants.
The absorbent articles of the present invention can be of various shapes and configurations depending on the intended end use, e.g., sanitary protection, including pantyliners and sanitary napkins specifically for use with thong underwear, surgical dressings or wipes, and the like. Additionally, the present absorbent articles can be incorporated into a disposable or limited use garment as an integral part thereof. For example, an absorbent article made according to the present invention can be a part of disposable training pants and similar garments.
The precise shapes of a pantyliner or sanitary napkin of the present invention may vary as desired. For thong-type underwear, the first portion is wider than the second portion. The midsection between the first portion and second portion may be tapered and narrow at a substantially continuous rate. The midsection may also be biconcave in shape or of a narrow, uniform width. In an alternative embodiment, the silhouette of the pantyliner or sanitary napkin may be substantially rectangular, dog bone, or peanut.
At least one flap may be adjacent to the posterior or second portion. Typically there are two flaps. The design of the flaps is not critical. The flaps may be extensions of the backsheet, the cover, or the cover and backsheet adhered or laminated together.
Absorbent articles also within the scope of this invention also include wound care articles such as bandages, including adhesive bandages. Adhesive bandages usually have a backsheet of perforated plastic or of a woven or knit fabric. The backsheet is covered completely or partially on one side with a pressure sensitive adhesive. An absorbent core is placed in the center of and adhered to the adhesive side of the backing material. The absorbent core typically lies between a cover, which contacts the skin and prevents the absorbent from sticking to the wound, and the backsheet.
Alternately, absorbent articles within the scope of this invention also include shoe liners. Shoe liners usually have a non-skid backing and an absorbent.